Prenatal Folic Acid Supplementation Found to Reduce Risk of Autistic Traits in Children of Women Taking AEDs

Prenatal folic acid supplements were found to reduce the risk of autistic traits in children born to women who were taking antiepileptic drugs while pregnant, according to a study published online on December 26 in JAMA Neurology.

The risk was less for these women compared with those who did not take folic acid supplements.

AEDs are known to inhibit folate absorption and metabolism in pregnant women, and exposure to AEDs in utero is known to increase the risk of autistic traits in children. Because of this, clinicians recommend that women on AEDs take high-dose folic acid supplements (5.0 mg/day). Until now, however, no study has examined the effect of folic acid supplementation on the risk of having a child with autistic traits.
“Fertile women using AEDs should take folic acid supplements continuously,” the study authors, led by Marte Bjørk, MD, PhD, of the department of neurology at Haukeland University Hospital in Bergen, Norway wrote.

For the study, researchers at several institutions in Norway assessed data on all Norwegian-speaking women who participated in the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa) between June 1999 and December 31, 2008. As part of that study, the women completed a series of questionnaires both during and after pregnancy that inquired, among other aspects of health, about folic acid supplementation; the researchers specifically assessed maternal folic acid supplementation four weeks before to 12 weeks after conception.

The researchers used information from the MoBa and the Medical Birth Registry of Norway to identify which women used AEDs, and which type(s), during pregnancy. The women also provided blood samples to the MoBa biobank, which the researchers used to assess plasma folate concentration at gestational weeks 17 to 19.

The researchers identified a total of 103,868 children who were born to women participating in the study who had available information on use of AEDs and of folic acid supplementation, and who were between 18 and 36 months old between March 1, 2016, through June 13, 2017. To assess the degree and frequency of autistic traits, the children were administered the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months of age and the Social Communication Questionnaire (SCQ) at 36 months of age by their parents.

The researchers found that a total of 335 children were exposed to AEDs during pregnancy. When the researchers compared maternal folic acid supplementation during pregnancy with the children’s health outcomes, they found that the risk for autistic traits was significantly higher among children whose mothers had not used folic acid supplements compared to those who had at both 18 months of age (adjusted OR [AOR], 5.9; 95%CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95%CI, 2.5-24.9). They found that the degree of autistic traits was inversely associated with maternal plasma folate concentrations (β=−0.3; p=0.03) and folic acid doses (β = −0.5; p<0.001). However, concentrations of AEDs were not associated with the degree of autistic traits.

Additionally, among women without epilepsy, the researchers found that the risks of autistic traits were lower at 18 months of age (AOR, 1.3; 95%CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95%CI, 1.5-1.9). Among 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95%CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95%CI, 0.4-16.6).
The findings indicate that the “risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status,” the study authors concluded.

The researchers noted a few limitations to their study. Among them, the M-CHAT and SCQ were administered by parents, not clinicians, although the results were stable across the instruments and across ages from 18 months to 36 months; and the statistical power was low for the association between AED concentrations and the risk of autistic traits for some AEDs, such as valproate sodium, so those associations must be interpreted cautiously.

Dr. Bjørk disclosed that she has received speaker’s and consultant’s honoraria from Novartis; no other disclosures were reported.